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Biomedical subjects

C Fegan

Publications and source records attributed to C Fegan.

At least 19 recordsLinked to original sources
PubMed2006

The SDF-1 G > A polymorphism at position 801 plays no role in multiple myeloma but may contribute to an inferior cause-specific survival in chronic lymphocytic leukemia.

The growth and circulation of B lymphocytes is largely under the control of bone marrow stromal cells, cytokines and chemokines. The gene responsible for the pivotal B cell growth factor, stromal derived factor-1 (SDF-1), has recently been shown to contain a single nucleotide polymorphism G > A at position 801 which leads to higher SDF-1 secretion. This polymorphism is common in the normal population and has been shown to play a potential role in the development of both HIV and non-HIV related non-Hodgkin's lymphoma. We therefore undertook a large single-centre study to ascertain its role in the pathogenesis of two other common B-cell malignancies, notably chronic lymphocytic leukemia (CLL- 197 patients) and multiple myeloma (126 patients). We show that the 801 G > A polymorphism plays no role in the incidence of multiple myeloma or CLL nor the outcome in multiple myeloma. By contrast, it trends towards an inferior cause-specific survival in CLL.

Adult↗
PubMed2004

Phase II study of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C alpha, in patients with previously treated low-grade non-Hodgkin's lymphoma.

BACKGROUND: The purpose of this study was to assess the efficacy and safety of ISIS 3521, an antisense phosphorothioate oligonucleotide to protein kinase C alpha in patients with relapsed low-grade non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Twenty-six patients received ISIS 3521 (2 mg/kg/day) as a continuous infusion over 21 days of each 28-day cycle. RESULTS: The median age of the patients was 53 years (range 37-77). Histological subtypes were low-grade follicular lymphoma (n = 22) and B-cell small lymphocytic lymphoma (n = 4). Twenty-one (81%) had stage III/IV disease. The median number of previous lines of chemotherapy was two (range one to six). A total of 87 cycles of ISIS 3521 were administered. Twenty-three patients were assessable for response. Three patients achieved a partial response. No complete responses were observed. Ten patients had stable disease. Grade 3-4 toxicity was as follows: neutropenia (3.8%) and thrombocytopenia (26.9%). CONCLUSIONS: ISIS 3521 has demonstrated anti-tumour activity in patients with relapsed low-grade NHL. There may be a potential role for this agent in combination with conventional chemotherapy for advanced low-grade lymphoma, and further trials are warranted.

Adult↗
PubMed2003

The platelet glycoprotein Ia/IIa gene polymorphism C807T/G873A: a novel risk factor for retinal vein occlusion.

Retinal vein occlusion (RVO) is associated with hyperhomocysteinaemia and the antiphospholipid syndrome-disorders known to contribute to both arterial and venous thrombosis. In both of these conditions and RVO, platelet activation occurs. Aspirin, not warfarin, is the most effective antithrombotic agent in RVO and, taken together, these observations suggest an important role for platelets in this common ocular thrombotic condition. Platelet glycoprotein Ia/IIa (GpIa/IIa) is an adhesion molecule mediating platelet-collagen interactions and is key to the initiation of thrombosis. Recently, the cellular density of this molecule was shown to be determined by two silent, linked polymorphisms (C807T/G873A) within the GpIa/IIa gene. There is evidence that some of the resulting genotypes are associated with thrombo-embolic disease. This study therefore aimed to establish the prevalence of the GpIa/IIa polymorphisms and the three commonest hereditary thrombophilic disorders (prothrombin gene G20210A (PT) mutation, Factor V Leiden (FVL), and the thermolabile methylene tetrahydrofolate reductase C677T (MTHFR) mutation) in patients with RVO and normal controls. The GpIa/IIa polymorphisms and thrombophilic abnormalities were all identified using the polymerase chain reaction.Our results show that the frequency of the GpIa/IIa polymorphisms was similar in our normal control population to previously published series. Patients with RVO, however, had only a 10% (4/40) frequency of the lowest risk subtype (CC/GG) compared to 37.5% (15/40) in the control group-P 0.0039. The incidence of the PT, FVL, and MTHFR thrombophilic mutations was not different between the two groups, but interestingly none of the 7/40 RVO cases with a PT, FVL, or MTHFR mutation had the low-risk GpIa/IIa genotype while all but one of the controls did-P<0.05. Thus, 17.5% of RVO patients harboured more than one prothrombotic abnormality. The principal difference between the RVO and control group was the very high incidence of the intermediate-risk GpIa/IIa subtype (CT/GA)-82.5 vs 50%, P&<0.05. These results suggest a major role for GpIa/IIa polymorphisms in the pathogenesis of RVO.

Adult↗
PubMed2003

Exercise in claudicants is accompanied by excessive thrombin generation.

BACKGROUND: exercise in IC leads to ischaemia-reperfusion injury of leg muscles and a systemic inflammatory response, but the effect of on coagulation is unknown. OBJECTIVE: to compare the effect of exercise on thrombin formation and fibrin turnover in patients with IC (n = 10), and age and sex matched smokers ([S] n = 5) and non-smokers ([NS] n = 5) without peripheral vascular disease. METHODS: blood was taken from subjects 60 and 30 min before, and 1, 5, 20, 40, 60 and 120 min after, treadmill exercise. Markers of thrombin generation (thrombin-antithrombin complexes [TAT] and prothrombin fragments 1 + 2 [PF1 + 2]) and fibrin turnover (D-dimer and fibrin degradation products [FbDP]) were assayed at each time point. RESULTS: following exercise, thrombin generation was significantly greater in the claudicant group compared to the control groups (Area Under Curve [AUC] post exercise IC vs S vs NS; TAT 3960 vs 1623 vs 1476 vs = 0.007 Kruskal-Wallis [KW]; PF1 + 2 163 vs 107 vs 123 p = 0.024 KW). Pre and post-exercise, fibrin turnover in claudicants was similar to smoking controls, but higher than non-smoking controls. (AUC post exercise IC vs NS; D-dimer 6340 vs 2754 p = 0.055 Mann-Whitney U[MW]; FbDP 45113 vs 21511 p = 0.009 MW). CONCLUSION: when compared to non-claudicants, exercise in IC is associated with excessive production of thrombin. Despite this, claudicants have a similar level of fibrin turnover suggesting a possible defect in fibrinolysis. This prothrombotic state may contribute to the excess thrombotic morbidity and mortality suffered by claudicants.

Aged↗
PubMed2003

Oral vitamin B12 can change our practice.

Oral vitamin B12 can provide an effective alternative to intramuscular injections, so giving patients a choice and reducing costs in primary care. This study investigated the effectiveness, safety, and acceptability of oral vitamin B12 as replacement therapy in patients with vitamin B12 deficiency in a city general practice population. Forty patients previously maintained on vitamin B12 injections were given 1000 micro g of oral cyanocobalamin daily for up to 18 months. All the patients maintained satisfactory serum B12 levels and showed normal haematology and neurology. Compliance and acceptability was excellent. The time for a change in practice has indeed arrived.

Administration, Oral↗
PubMed2002

Thrombophilia and chronic venous ulceration.

It is known that thrombophilia (TP) is a risk factor for deep venous thrombosis (DVT), and that DVT predisposes to chronic venous ulceration (CVU). However, the relationship between TP and CVU has not been well studied. Review of the literature reveals that the prevalence of TP in CVU patients is high--similar to the prevalence found in patients with a history of DVT. This is despite many patients with CVU having no clear history, or duplex evidence of previous DVT. TP may predispose to CVU by leading to macro- or micro-vascular thrombosis. This association raises several issues regarding the investigation, prevention and management of patients with venous disease.

Chronic Disease↗
PubMed2002

ATM mutations in sporadic lymphoid tumours.

Patients with the autosomal recessive disorder ataxia telangiectasia (A-T) show the biallelic inactivation of the ataxia telangiectasia mutated (ATM) gene. A-T patients exhibit a predisposition to the development of a wide range of lymphoid tumours, suggesting that the ATM protein normally plays an important role in the prevention of both T and B cell malignancies. The ATM protein is a 370 kDa protein kinase implicated in the integration of different cellular responses to particular forms of DNA damage. Several recent studies have reported the possibility that the ATM gene can act as a tumour suppressor gene in non A-T individuals. Frequent ATM inactivation was confirmed in three sporadic lymphoid tumours of mature phenotype: T cell prolymphocytic leukaemia (T-PLL), B-cell chronic lymphocytic leukaemia (B-CLL) and mantle cell lymphoma (MCL). Here, we provide a summary of the published ATM mutations in sporadic lymphoid tumours, including our own study on the role of ATM mutations in the pathogenesis of sporadic B-CLL. The published results suggest possible differences in the origin, the nature and distribution of ATM mutations between sporadic B-CLL, MCL and T-PLL. While ATM mutations in mature B cell tumours (B-CLL and MCL) represent a mixture of missense and truncating errors distributed across the whole of the ATM coding sequence, mutations in sporadic T-PLL appear to be predominantly missense, clustering in the region encoding the PI-3 kinase catalytic domain of the protein. The reason for this difference is unclear, but the difference itself supports the notion that the pathogenesis of B and T cell tumours on an ATM deficient background might be different. In addition, in both B-CLL and MCL ATM mutation carriers have been reported, raising the possibility that ATM mutation carriers may have an increased risk of developing these tumours. The existence as well as magnitude of the risk, however, remains to be established. Furthermore, our own studies indicate that the presence of ATM mutations in sporadic B-CLL causes a distinctive defect in response to DNA damaging agents, offering a possible explanation for the poor response of ATM mutant tumours to standard treatment. Therefore, one of the future challenges will be to devise strategies to bypass the existing defect in response to DNA damage and activate apoptosis in ATM mutant sporadic lymphoid tumours.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2001

Flavopiridol circumvents Bcl-2 family mediated inhibition of apoptosis and drug resistance in B-cell chronic lymphocytic leukaemia.

Flavopiridol, a synthetic flavone, is currently under clinical investigation for the treatment of B-cell chronic lymphocytic leukaemia (B-CLL). In this study, we examined the in vitro effects of flavopiridol and fludarabine on B-CLL cells from 64 patients (36 treated and 28 untreated) in terms of apoptosis induction and Bcl-2 family expression. Both flavopiridol and fludarabine induced apoptosis in all the samples tested with mean LD(50) values (+/- SD) of 59.7 nmol/l (+/- 36.5) and 6.2 micromol/l (+/- 7.5) respectively. Mean flavopiridol LD(50) values were not significantly different between the treated and untreated patient groups (P = 0.35), whereas the fludarabine LD(50) values were significantly higher in the previously treated patient group (P = 0.01). Bcl-2 and Mcl-1 expression were downregulated in both flavopiridol and fludarabine-induced apoptotic cells, but the increase in Bax expression that accompanied fludarabine-induced apoptosis was not evident in flavopiridol-treated cells. In addition, Bcl-2:Bax ratios were not predictive of flavopiridol cytotoxicity (P = 0.82), whereas they were highly predictive of in vitro responsiveness to fludarabine (P = 0.001). Overall, these findings suggest that flavopiridol exerts its cytotoxic effect through a novel cell-death pathway that is not subject to the Bcl-2 family mediated resistance mechanisms that reduce the efficacy of many conventional chemotherapeutic drugs.

Antineoplastic Agents↗
PubMed2001

Molecular abnormalities in B-cell chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia is the commonest adult leukaemia, however the pathogenesis is largely unknown. Since the 1980s specific chromosomal abnormalities have been identified, of which the commonest are deletions of chromosomes 6q, 11q23, 13q14 and 17q13 and trisomy 12. The search for the responsible oncogenes at these sites has proved to be extremely frustrating. There are many oncogenes at 11q23 but the exact gene(s) responsible have yet to be identified. Germline abnormalities of the ATM gene occur in about 18% of patients compared to a normal population carriage of 0.5% but not all studies agree that ATM is the gene responsible. Unfortunately, despite the identification of various minimally deleted regions and the full sequencing of 13q14 no oncogenes have been identified. All original studies suggested the presence of a autosomally recessive tumour suppressor gene at this site but more recent studies suggest this may not be the case and the pathogenesis is more complex than first thought. Similarly, no genes have been identified at 6q or on chromosome 12. We know that the p53 tumour suppressor gene at 17p13 is an important prognostic indicator but it occurs in a minority of patients (about 15%), usually in patients with advanced disease, and therefore probably is not of aetiological importance.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2001

The outcome of ambulatory DVT management using a multidisciplinary approach.

Low molecular weight heparins (LMWHs) have been demonstrated to be at least as safe and effective as unfractionated heparin (UFH) in the initial management of deep vein thrombosis (DVT). However, the effectiveness of using LMWH in the ambulatory management of DVT in a 'real-life' setting has yet to be evaluated. This multicentre retrospective study involving 697 patients considers the outcome data of patients under- going ambulatory DVT treatment with tinzaparin (Innohep(R), Leo Pharmaceuticals, Risborough, Buckinghamshire, UK). During the 6 months following presentation, 17 (2.5%) patients had confirmed thromboembolic complications, of which 14 occurred subsequent to the initial LMWH treatment phase ('late'). There were no deaths in this group. Bleeding complications were reported in 23 (3.4%) patients, with 13 of these being classified as 'late'. Of these, two events were considered major resulting in hospitalization and death. Hospitalization for all causes was 6.8% (45 patients) with 32 patients being admitted for thromboembolic or bleeding complications. Overall mortality was 6.7%. These results compare favourably with published clinical trial data. This study demonstrates that ambulatory treatment of proven DVT with LMWH is both safe and effective.

Adolescent↗
PubMed2000

Thrombophilia, polymorphisms, and vascular disease.

Thrombophilia traditionally refers to rare inherited defects leading to enhanced coagulation, especially of the venous system. In recent years, a broader search for genetic polymorphisms of prothrombotic genes has been carried out to determine the relative impact on venous and arterial thrombosis. The bulk of evidence is drawn from numerous, often small, heterogeneous, case control association studies, with a variety of end points (deep venous thrombosis, myocardial infarction, or stroke). The data are often conflicting and inconclusive with only factor V Leiden and prothrombin polymorphisms having clear associations with venous thrombosis. Many of the polymorphisms interact with established cardiovascular risk factors, in particular smoking, to increase greatly the risk of a thrombotic episode. Future studies will need to consider the confounding factors of sample size, race, and clinical end points as well gene-environment interactions.

Blood Coagulation Factors↗
PubMed1999

Haemostatic and fibrinolytic responses to bone marrow transplantation.

Thrombin and plasmin activation markers were serially measured in 80 patients undergoing bone marrow transplantation (BMT). There were prothrombotic and fibrinolytic responses observed during autograft and allograft BMTs. Thrombin-antithrombin and prothrombin fragment F1+2 levels increased from day -7 to -3 (P<0.0001) from 3.7 to 7 ng/ml and 1.2 to 1.63 nmol/l, respectively. A rise in plasmin-antiplasmin levels occurred between days 4 and 14 (P< 0.0004), from 393 ng/ml on day -7 to a peak of 795 ng/ml on day 11. No correlation between reduced protein C levels post-BMT and a prothrombotic state was observed.

Adolescent↗
PubMed1998

Parenteral glutamine protects hepatic function during bone marrow transplantation.

Hepatic veno-occlusive disease (VOD) of the liver is a common complication following high-dose cytotoxic therapy for bone marrow transplantation (BMT). The major pathological changes are seen in centrilobular (zone 3) hepatocytes and adjacent endothelium. Glutathione (GSH) becomes depleted following chemotherapy and experimental evidence suggests reduced levels predispose to centrilobular hepatocyte and endothelial cell injury. Animal studies have shown that glutamine infusions can maintain GSH levels and protect against free radical injury. We have prospectively studied the effect of glutamine supplementation during BMT. Thirty-four patients undergoing BMT were randomised to receive either glycl-L-glutamine (n = 18) or an isonitrogenous mixture of non-essential amino acids (n = 16). Glutamine was shown to significantly preserve protein C (days +4 and +7, P < 0.05) and albumin levels (days 0 and +4, P < 0.02). Markers of thrombin and plasmin generation (thrombin-antithrombin, prothrombin fragment F1+2 and plasmin-antiplasmin levels) were not significantly changed between the two groups. These findings suggest that glutamine preserves hepatic function but does not alter thrombin or plasmin generation during BMT. Previous studies have shown reductions in protein C, albumin, factor X and factor VII levels post BMT. Falling protein C levels have been shown to be predictive of severe VOD. These data suggest a role for glutamine in the protection of hepatic function following BMT.

Adolescent↗
PubMed1995

All trans retinoic acid enhances human LAK activity.

All trans retinoic acid has various effects on normal and malignant cells. Lymphokine-activated killer (LAK) activity can be derived from T lymphocytes and natural killer cells. This study shows that all trans retinoic acid significantly enhances this activity by increasing production of tumour necrosis factor and gamma interferon, which results in enhanced expression of the p55 part of the interleukin 2 receptor. This effect is dependent on the concentration of all trans retinoic acid and the length of time of culture.

Cells, Cultured↗